Glaucoma is an ocular disease having the characteristic of a visual functional disorder which causes a transient or permanent visual field defect and decreased vision. This is derived from that since an aqueous humor is accumulated by a circulatory disorder of an aqueous humor, and an intraocular pressure is continuously increased, an optic nerve is compressed. Decrease in an intraocular pressure is effective for treatment of glaucoma and, in order to decrease an intraocular pressure, for example, drug treatment (eye drops, internal remedy, infusion treatment), laser treatment, or operation treatment is performed.
Previously, among prostaglandins (PGs) which are physiologically active substances, as those that decrease an intraocular pressure, PGFs and PGIs are known. Development of a drug for treating glaucoma or ocular hypertension is being progressed using derivatives of them, and there are some drugs which are actually sold (e.g. latanoprost etc.). However, the existing glaucoma treating drug alone is insufficient in intraocular pressure lowering action and, in at site of glaucoma treatment, since administration at a high concentration, or therapy of joint use of drugs having different mechanisms of action are being performed seeking stronger intraocular pressure lowering action, manifestation of side effects is feared. For this reason, drugs having stronger intraocular pressure lowering action, and high safety are desired.
Meanwhile, as the prior art of the present invention compound, the following PG derivatives are exemplified.
As a PG derivative having a bicyclic skeleton, for example, a compound represented by the formula (a):
(wherein a ring Aa represents
(wherein
represents α-configuration, β-configuration or a mixture thereof) etc., a ring Ba represents
(wherein, ra represents 0, 1 or 2) etc., Ya represents an ethylene group, a vinylene group or an ethynylene group, Za represents —(CH2)ma— (wherein ma represents 3, 4 or 5) etc., R1a represents —COOR8a (wherein R8a represents a hydrogen atom or an alkyl group of a C1-12 alkyl group etc.) etc., R2a represents a hydrogen atom etc., R3a represents a single bond or a C1-5 alkylene group etc., R4a represents a C1-8 alkoxy group, a halogen atom, a trifluoromethyl group, a phenoxy group optionally substituted with a C1-8 alkyl group, etc., and R5a represents a hydrogen atom etc.) is disclosed as a PGI1 analogue, and described to be useful for contraception or menstruation control (see Patent Literature 1).
In addition, a compound represented by the formula (b):
(wherein Lb represents —(CH2)db— (wherein db represents 1 to 5) etc., Q2b represents 0 etc., R1b represents —COOR19b (wherein R19b represents a C1-12 alkyl group or a hydrogen atom etc.) etc., a ring R22b represents
(wherein R4b represents a hydrogen atom etc.) etc., R25b represents
(wherein R5b and R6b represent a hydrogen atom etc., Zb represents —O— etc., Tb represents a C1-4 alkyl group, fluorine, chlorine, trifluoromethyl or —OR7b— (wherein R7b represents a C1-4 alkyl), sb represents 0, 1, 2 or 3, and Xb represents
(a part of definitions of groups was extracted)) (see Patent Literature 2) is known.
Further, a compound represented by the formula (c):
(wherein Rc is selected from (a) a free carboxy group and an esterified carboxy group, etc., Z1c is hydrogen or a halogen, pc is 0 or an integer of 1 to 7, qc is 1 or 2, R1c is hydrogen, hydroxy, etc., Yc is selected from —CH2—CH2—,
(wherein Z2c is hydrogen or a halogen) etc., one of R2c and R5c is hydrogen, a C1-6 alkyl, etc., and the other is hydroxy, etc., R3c and R4c are the same or different and each are hydrogen, a C1-6 alkyl or fluorine, n1c and n2c are the same or different and each are 0 or an integer of 1 to 6, Xc is selected from the group consisting of —O—, —S— and —(CH2)mc— (wherein mc is 0 or 1), and R6c is selected from the group consisting of hydrogen, a C1-4 alkyl, and an aryl unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen and a C1-6 alkyl, etc.) is known (see Patent Literature 3).
Meanwhile, it has been reported that agonistic activity on an IP receptor among PG receptors causes hyperemia and rise in an aqueous humor protein, and inducement of stimulation on eyes has been feared (see Non-Patent Literatures 1 and 2). For this reason, since the compounds described in Patent Literatures 1, 2 and 3 which are PGI2 derivatives have agonistic activity on an IP receptor, there is a probability that property of stimulating eyes etc. are induced.
In addition, agonistic activity on EP2 and EP4 receptors is known to be involved in inflammatory response of eyes (see Non-Patent Literature 3).
The present invention compound is a compound which has low agonistic activity on an IP receptor and EP2 and EP4 receptors, and has selective agonistic activity on an FP receptor, but there is neither the description nor the suggestion regarding such a characteristic (selectivity) in any prior arts.